Table 1.

Potential drug targets, repurposed drugs, and their mode of action to limit leishmaniasis.

Leishmania Species	Pathway	Drug Target	Potent Drug Candidate	Mode of Action	Reference
L. braziliensis	Sterol Biosynthetic Pathway	Squalene epoxidase	JS87	annulation of quinoline and oxindole scaffolds	[25]
L. infantum	Sterol Biosynthetic Pathway	Squalene epoxidase	spiro[cyclohexanone-oxindoles]	Inhibition of phosphodiesterase and tyrosine kinase	[23]
L. donovani	Sterol Biosynthetic Pathway	Squalene epoxidase	spiro[indole-3,3′-pyrrolizidine]-2-one	inhibitor of bisubunit DNA topoisomerase IB	[24]
L. braziliensis	Sterol Biosynthetic Pathway	sterol-14-α-demethylase	6-ethyl-2-phenylquinoline	disruption of mitochondrial electrochemical potential and alkalinization of acidocalcisomes	[32]
L. donovani	Sterol Biosynthetic Pathway	HMGR enzyme	Mevastatin	Inhibits HMGR activity	[17]
L. donovani	Sterol Biosynthetic Pathway	Sterol alpha-14 demethylase	Avodart	Avodart-induced ROS caused apoptosis-like cell death in the parasites	[29]
L. major	Sterol Biosynthetic Pathway	14-lanosterol demethylase	fenarimol	destabilization of membrane structure by inhibiting 14α sterol demethylase.	[37]
L. donovani	Sterol Biosynthetic Pathway	HMGR enzyme	Glycyrrhizic acid	inhibiting the HMGR enzyme	[40]
L. donovani	Purine Salvage Pathway	mRNA translation	5-fluorouracil 4-thiouracil	binds to RNA and inhibits cell development	[46]
L. infantum	Purine Salvage Pathway	mRNA translation	pyrazolo [3,4-d] pyrimidine	binds to RNA and inhibits cell development	[47]
L. donovani	Glycolytic Pathway	GAPDH	artesunate	targeting parasites’ glycolytic enzymes mainly Glycerol-3-phosphate dehydrogenase	[53]
L. donovani	Glycolytic Pathway	GAPDH	quinine	targeting parasites’ glycolytic enzymes mainly Glycerol-3-phosphate dehydrogenase	[53]
L. donovani	Glycolytic Pathway	GAPDH	mefloquine	targeting parasites’ glycolytic enzymes mainly Glycerol-3-phosphate dehydrogenase	[53]
L. major	Glycolytic Pathway	phosphoglycerate kinase	Suramin	inhibition of cytosolic phosphoglycerate kinase from	[55]
L. major	Glycosyl phosphatidyl inositol	mannosyltransferase	N-4-(-5(trifluromethyl)-1-methyl-1H benzo[d]imidazole-2 yl) phenyl)	inhibit mannosylation of glycosyl phosphatidyl Inositol	[69]
L. donovani	Folate Biosynthesis Pathway	DHFR	Methotrexate (MTX, 1),	Inhibit DHFR	[75]
L. donovani	Folate Biosynthesis Pathway	DHFR	cycloguanil	Inhibit DHFR	[75]
L. donovani	Folate Biosynthesis Pathway	DHFR	trimethoprim (TMP, 2)	Inhibit DHFR	[75]
L. donovani	Folate Biosynthesis Pathway	DHFR	ZINC57774418 (Z18)	Inhibits DHFR activity	[76]
L. donovani	Folate Biosynthesis Pathway	DHFR	ZINC69844431 (Z31)	Inhibits DHFR activity	[76]
L. donovani	Folate Biosynthesis Pathway	DHFR	ZINC71746025 (Z25)	Inhibits DHFR activity	[76]
L. donovani	Folate Biosynthesis Pathway	DHFR	and D11596 (DB96)	Inhibits DHFR activity	[76]
L. donovani	Folate Biosynthesis Pathway	DHFR	3,4-dihydropyrimidine-2-one	Inhibits DHFR activity	[77]
L. donovani	Folate Biosynthesis Pathway	DHFR	5-(3,5-dimethoxybenzyl) pyrimidine-2,4-diamine	Inhibits DHFR activity	[77]
L. major	Folate Biosynthesis Pathway	PTR1	thiosemicarbazones and 1,2,4-triazoles	Inhibit DHFR and PTR activity	[85]
L. donovani	Folate Biosynthesis Pathway	DHFR and PTR1	2-(4-((2,4-dichlorobenzyl)oxy)phenyl)-1H-benzo[d]imidazole	dual inhibitors of DHFR-TS and PTR1	[86]
L. donovani	Folate Biosynthesis Pathway	DHFR and PTR1	2-(4-((2,4-dichlorobenzyl)oxy)phenyl)-1H-benzo[d]imidazole-1H-benzo[d]oxazole	dual inhibitors of DHFR-TS and PTR1	[86]
L. major	Folate Biosynthesis Pathway	PTR1	Sophoraflavanone G	Inhibits PTR1 activity	[87]
L. chagasi	Folate Biosynthesis Pathway	DHFR and PTR1	2,4-diaminoquinazoline	dual inhibitors of DHFR-TS and PTR1	[88]
L. braziliensis, L. Mexicana, and L. amazonensis	Folate Biosynthesis Pathway	PTR1	2-arylquinazolin-4(3H) ones	Inhibits PTR1 activity	[92]
L. infantum	Trypanothione pathway	TR	[RDS 777] (6-(sec-butoxy)-2-((3-chlorophenyl) thio) pyrimidin-4-amine)	forms hydrogen bonds with the catalytic residues Glu466’, Cys57, and Cys52, limiting trypanothione binding and preventing its reduction	[99]
L. donovani	Trypanothione pathway	TR	trichloro [1,2-ethanediolato-O,O’]-tellurate (AS101)	Inhibits TR by forming thiol bonds with cysteine residues of TR., thus inducing ROS mediated apoptosis	[100]
L. infantum	Trypanothione pathway	TR	pyrrolopyrimidine	Disrupting the homodimeric interface trypanothione disulfide reductase	[101]
L. infantum	Trypanothione pathway	TR	5-6-5 imidazole-phenyl-thiazole-helix-mimetic scaffolds	Disrupting the homodimeric interface trypanothione disulfide reductase	[101]
L. infantum	Trypanothione pathway	TR	Triazole-phenyl-thiazoles	Disrupting the homodimeric interface trypanothione disulfide reductase	[102]
L. braziliensis	Trypanothione pathway	TR	resveratrol analogues	Induce ROS by inhibiting TR activity	[103]
L. mexicana	Trypanothione pathway	TR	N-(6-quinolinemethyl)-3-pyrazole carboxamide	formation of hydrogen bonds with the active site of TR	[105]
L. donovani	Trypanothione pathway	TR	β-sitosterolCCL	Inhibit TR activity	[108]
L. infantum	Trypanothione pathway	TR	(-)-Epigallocatechin 3-O-gallate (EGCG)	a competitive inhibitor of the trypanothione substrate.	[110]
L. infantum	Trypanothione pathway	TR	3-Methoxycarpachromene	Inhibits TR activity	[107]
L. donovani	Hypusine pathway	spermidine synthase	hypericin	decrease spermidine availability and induce ROS	[121]